5 years ago

{beta}2-Adrenoreceptor is a regulator of the {alpha}-synuclein gene driving risk of Parkinsons disease

Dennis J. Selkoe, Marcie A. Glicksman, Barbara J. Caldarone, Peter Heutink, Tim Bartels, Yang K. Xiang, Kristine M. Abo, Elizabeth Long, Adrian Flierl, Bing Xu, Ming Jin, Kjetil Bjørnevik, Vikram Khurana, Shuchi Mittal, Trond Riise, Birgitt Schüle, Jean-Christophe Rochet, Xianjun Dong, David S. Park, Patrizia Rizzu, Anders Engeland, Joseph J. Locascio, Clemens R. Scherzer, Doo Soon Im

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson’s disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

Publisher URL: http://science.sciencemag.org/cgi/content/short/357/6354/891

DOI: 10.1126/science.aaf3934

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